# Impact of peripheral nerves on mesenchymal cell fate in extremity trauma

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $576,704

## Abstract

Project Summary
Heterotopic ossification (HO) is characterized by the aberrant osteochondral differentiation of tissue resident
mesenchymal progenitor cells. HO afflicts nearly 20% of extremity trauma, amputation and large surface area
burn patients and is clinically preceded by pain. Currently, no treatments exist to prevent initiation, reverse
disease progression, or limit pain through efficacious, non-opioid mechanisms. In the course of analyzing our
validated trauma-induced HO model, we observed nerve ingrowth as an early response to trauma. Using a
unique human traumatic HO dataset of early and late HO lesions, we have confirmed this early and maladaptive
nerve ingrowth precedes HO. Additionally, we discovered that surgical denervation potently inhibits early stages
of HO formation. In follow up studies, we uncovered the role of nerve growth factor (NGF) as the primary stimulus
of this pre-HO nerve ingrowth and, unexpectedly, that perivascular cells (pericytes and vascular smooth muscle
cells) appear to be the primary source of this neurotrophin. To elucidate the role of NGF induced nerve ingrowth
on HO, we performed complementary studies which suggest that nerve ingrowth may activate mesenchymal
progenitor cell TGFβ1 signaling to drive aberrant chondrogenic differentiation among local mesenchymal
progenitor HO precursor cells. These observations have led to our central hypothesis that perivascular derived
NGF stimulates TrkA-expressing sensory dendrite ingrowth into the HO site, which in turn releases TGFβ1 to
stimulate mesenchymal progenitor cell osteochondral differentiation. As such, the following aims are proposed:
Aim 1: Define the role of perivascular NGF in controlling sensory nerve ingrowth at sites of HO
initiation and progression. Using established animal models, we hypothesize that tissue-specific deletion of
Ngf in pericytes (Pdgfrb-CreERT2;Ngffl/fl) or vascular smooth muscle cells (vSMCs; Myh11-CreERT2;Ngffl/fl) will
abrogate peripheral nerve ingrowth and HO formation at sites of trauma.
Aim 2: Test the role of TGFβ1 signaling in sensory nerve-mesenchymal progenitor cell cross talk in
HO. Using established animal models, we hypothesize that sensory nerves positively regulate mesenchymal
progenitor cell osteochondral differentiation through a TGFβ1 dependent process.
Aim 3: Define a potential role for anti-NGF neutralizing antibodies as a novel HO therapeutic
intervention. We hypothesize that Fasinumab (an NGF neutralizing antibody) represents a dual analgesic and
negative regulator of HO disease progression, which blunts pathologic nerve ingrowth.

## Key facts

- **NIH application ID:** 10836347
- **Project number:** 5R01AR079171-08
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** AARON W JAMES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $576,704
- **Award type:** 5
- **Project period:** 2017-08-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10836347

## Citation

> US National Institutes of Health, RePORTER application 10836347, Impact of peripheral nerves on mesenchymal cell fate in extremity trauma (5R01AR079171-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10836347. Licensed CC0.

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